The present invention relates to 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives, a process for the preparation of the derivatives and anti-tumor agents containing the derivatives as active ingredients thereof. More particularly, the present invention relates to new 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula: ##STR2## wherein R stands for an alkyl group, an alkoxy group or a halogen atom, m for zero or an integer of 1-3, and n for an integer of 1-14, with the proviso that when m is 2 or 3, R's may be the same or different and that when m is 2 and the adjacent two R's are alkoxy groups, the two alkyl moieties of the alkoxy groups may be combined to form together with the two adjacent oxa bridging members an alkylenedioxy group as a whole, a process for the preparation of the derivatives wherein a 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine is reacted with a benzoyl halide derivative, and anti-tumor agents containing the 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives as active ingredients thereof.
In the field of chemotherapy, the major public attention is now directed to the development of effective anti-tumor agents. Heretofore, various kinds of 5-fluorouridine derivatives have been developed as anti-tumor agents. However, all of these derivatives are quite unsatisfactory as they are either poor in the inherent anti-tumor activity or exhibit strong toxicity. 2'-Deoxy-5-fluorouridine (referred to hereinafter simply as FUDR) is already used as an anti-tumor agent but this compound is exceptionally high in toxicity for medication and has a narrower safety region. In addition, this compound is subject to a considerable limitations in actual therapeutic applications since the mode of administering this compound is limited only to intraarterial injection, or in other words, this compound cannot be administered orally [Physicians' Desk Reference, p. 1387 (1978)].
Heretofore, extensive researches have been made by C. Heidelberger et al. on the mechanism of anti-tumor activity of FUDR and a variety of studies have also been made by them to develop new FUDR derivatives which are devoid of such drawbacks and possess a high level of anti-tumor activity of chemical modification of FUDR. As a result of the studies 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine (referred to hereinafter simply as acetyl-FUDR) as one of the new chemically modified FUDR derivatives was found to possess such a property that this compound is hardly decomposed in living body, thus suggesting the possibility of oral administration [Cancer Research, 23, 49 et seq. (1963)]. As a result of experiments made on anti-tumor activity of the acetyl-FUDR, however, this compound is evaluated to be almost equivalent in anti-tumor activity to FUDR or rather poor in effectiveness [Biochem. Pharmacology, 14, 1605 et seq., (1965); Cancer Research, 23, 420 et seq. (1963)]. Thus, the acetyl-FUDR is still unsatisfactory as a practically effective anti-tumor agent.
A number of researches have thus been made on FUDR derivatives and results of the researches are summarized, for example, as a correlation between the chemical structure and the anti-tumor activity of FUDR and its derivatives in Cancer Research, 30, 1555-6 (1970).
In this reference, three enzymatic activities which were found to keys to the development of anti-tumor activity as a result of clarifying the mechanism of anti-tumor activity exhibited by FUDR are taken up as subjects and an explanatory diagram is given to show that positions and what structures of the FUDR molecule are necessary for exhibiting anti-tumor activity. In this reference, however, it is stated that the nitrogen atom in 3-position of the uracil (pyrimidine or pyrimidione) ring of FUDR should not be substituted.
3',5'-Dialkyl esters of FUDR are also reported as derivatives of FUDR but they are still unsatisfactory with respect to anti-tumor activity and toxicity [Biochem. Pharmacology, 14. 1605-1619 (1965), ibid. 15, 627-644 (1966)]. Recently, FUDR and acetyl-FUDR derivatives have been reported wherein the hydrogen atom bonded to the 3-nitrogen atom on the uracil ring is substituted by a specific aroyl group (UK Patent Appln. No. 2,025,401 published on Jan. 23, 1980 and European Patent Appln. No. 9,882 published on Apr. 16, 1980). However, further enhancement in anti-tumor activity is desired also in these compounds. Thus, there is a great demand for developing new FUDR derivatives which possess strong anti-tumor activity with weak toxicity and are suited for oral administration without the necessity of troublesome intraarterial or intravenous injection.